1. Technical Field
The present invention relates to the treatment, alleviation, prevention or reduction in the incidence of symptoms, diseases or conditions resulting from or associated with enteroviruses, more particularly the enteroviral infections they cause.
2. Description of the Related Art
The Picornaviridae family of viruses, containing the genus Enterovirus, are nonenveloped viruses with a single-stranded RNA genome of positive polarity.
Serotypes of the genus Enterovirus were originally classified into three groups, namely the polioviruses, group A and B coxsackieviruses and echoviruses. Since 1969 new enterovirus serotypes, that might otherwise have fallen within these three groups, have been named numerically with an enterovirus (EV) number starting from 68 (i.e. EV68) (see for example Knipe, D M, Howley P M et. al. eds Fields Virology 5th ed. Volume 1 Section II Philadelphia, Pa.: Lippincott Williams & Wilkins (2007)). Under a new classification scheme from the International Committee on Taxonomy of Viruses (ICTV) the following ten species are now included in the genus Enterovirus: Human enterovirus A (HEV-A), Human enterovirus B (HEV-B), Human enterovirus C (HEV-C), Human enterovirus D (HEV-D), Bovine enterovirus, Porcine enterovirus B, Simian enterovirus A, Human rhinovirus A, Human rhinovirus B and Human rhinovirus C (see for example ICTV Master Species List 2009 Version 4). The four species HEV-A, HEV-B, HEV-C and HEV-D include the polioviruses, group A and B coxsackieviruses, echoviruses and enterovirus serotypes EV68 onwards. Within the species HEV-A, HEV-B, HEV-C and HEV-D the enterovirus serotypes may accordingly be categorised as non-polio enterovirus serotypes (an expression used herein to embrace group A and B coxsackieviruses, echoviruses and enterovirus serotypes from EV68 onwards) and poliovirus serotypes.
Prior to 2008 the rhinoviruses did not fall within the genus Enterovirus and were given their own genus Rhinovirus, of the Picornaviridae family. Rhinoviruses are acid-labile viruses which replicate in the nasopharynx and may also replicate in the lower respiratory tract whereas the members of the species HEV-A, HEV-B, HEV-C and HEV-D replicate in the alimentary tract and accordingly retain infectivity at pH values of 3.0 and sometimes lower.
Following replication in the alimentary tract, members of the species HEV-A, HEV-B, HEV-C and HEV-D typically enter the bloodstream where they may affect a variety of tissues and organs thereby causing a diversity of conditions or diseases. Potential targets include the skin and central nervous system (CNS). Transmission of the virus is usually by the faeco-oral or respiratory route and is increased by poor hygiene and overcrowded living conditions.
Members of the species HEV-A, HEV-B, HEV-C and HEV-D, are responsible for a wide range of viral infections which cause or are associated with a wide variety of symptoms, diseases or conditions such as viral meningitis, encephalitis, gastroenteritis, pancreatitis, fever, paralysis, myocarditis/pericarditis, pneumonia, bronchiolitis, croup, sepsis and hand foot and mouth disease and have even been suspected of having a role in the onset of type 1 diabetes. In some instances enteroviral infections may result in severe, life-threatening complications and even death. Children, especially those under the age of five, are the most susceptible to enteroviral infections.
The poliovirus subgenus classification comprises three serotypes of polioviruses, numbered PV1, PV2 and PV3. Children under the age of five are at most risk of the highly infectious disease which may lead to irreversible paralysis usually of the legs and in some cases death due to immobilisation of breathing muscles. There is no known cure for polio although two forms of polio vaccine, namely the Salk inactivated polio vaccine (IPV) and the Sabin live attenuated vaccine (OPV, oral polio vaccine), may be administered as a preventative measure. In recent times a global effort to eradicate the disease by polio vaccination in early childhood has seen the incidence of polio cases decrease (down by approximately 99% in the period 1988 to 2008). By 2008 only Afghanistan, India, Nigeria and Pakistan remain polio-endemic. Unfortunately, children in all countries still remain at risk of contracting the disease as long as any child has the infection. This risk was most recently highlighted when a number of polio-free countries were re-infected with imports of the disease in 2003 to 2005 and in 2008 to 2009.
The non-polio enteroviruses within the species HEV-A, HEV-B, HEV-C and HEV-D comprise the subgenera coxsackieviruses A (such as serotypes 1-22 and 24), coxsackieviruses B (such as serotypes 1-6), echoviruses (such as serotypes 1-7, 9, 11-27, 29-34) and the more recently classified enteroviruses (such as serotypes EV68 onwards). In the US alone it is estimated that non-polio enteroviruses within the species HEV-A, HEV-B, HEV-C and HEV-D are responsible for approximately 10-20 million cases of symptomatic infections annually. The incidence of infections is generally influenced by seasons and climates. Generally, countries which experience temperate climates are likely to observe higher incidences of infections in the summer and autumn months whereas countries with subtropical and tropical climates are likely to experience infections year-round. An increasing number of pandemics caused by EV71 infections have been reported in recent times which are of particular concern given their association with fatalities. The EV71 virus' propensity to cause severe neurological conditions or diseases is also of particular concern. Non-polio enteroviral infections, such as EV71 infections, are therefore an ever increasing public health concern given the risk of life-threatening complications associated with the symptoms, diseases and conditions they cause and the lack of an approved effective therapy for their prevention or treatment.
There are no approved antiviral agents or vaccines for the treatment or prevention of infections caused by serotypes of one or more of the species HEV-A, HEV-B, HEV-C and HEV-D, with the exception of the two prophylactic forms of polio vaccine. Accordingly, there remains an ongoing need for an antiviral agent effective against serotypes of one or more of the species HEV-A, HEV-B, HEV-C and HEV-D, the enteroviral infections they cause and the symptoms, conditions or diseases arising from them.